One-Pot Synthesis of 1-Substituted 1H-Isochromenes by Combining Brønsted Acid with Silver Catalysis

^§ These authors contributed equally to this work.

Dedicated to Professor Gerhard Bringmann on the occasion of his 65th birthday

Abstract

A one-pot synthesis of 1-substituted 1H-isochromenes employing various 2-alkynyl-benzaldehydes and ketones as substrates under a combination of Brønsted acid and silver catalysis has been developed. The isochromenes, which are present as important heterocyclic core structures in many bioactive and natural compounds, are obtained in medium to excellent yields with diastereomeric ratios of up to 9:1. A first enantioselective variant has also been tested.

Key words

isochromene - Brønsted acid catalysis - silver catalysis - organocatalysis - one-pot synthesis

Isochromenes are a common heterocyclic motif in natural products and bioactive compounds.[1] For example, compound I, containing the isochromene core structure, has been studied as an anti-inflamatory agent.[2] Chloroquinocin (II)[3] and alnumycin-D (III)[4] have shown activity as antibacterial and antimicrobial agents, respectively. Benzosimuline (IV) has been isolated as a natural product from the plant Formosan Zanthoxylum simulans and has been found to be active against platelet aggregation[5] (Figure [1]). In consequence, it is very important to develop new methods for the synthesis of isochromene derivatives. Various methods for the synthesis of 1-substituted 1H-isochromenes have already been reported, such as metal-catalyzed cycloisomerizations of 2-alkynylaldehydes in the presence of suitable carbon-[6] or oxygen-nucleophiles.[7] In addition, Yamamoto and co-workers reported on the treatment of 1-alkoxy 1H-isochromenes with a Lewis acid generating a benzopyrylium ion, which can be trapped by suitable nucleophiles leading to 1-substituted 1H-isochromene derivatives[8] (Scheme [1]). In view of the importance of the title heterocycles, one-pot syntheses of substituted 1H-isochromene derivatives are very desirable because the one-pot multicomponent domino synthesis of organic molecules has many advantages.[9]

Figure 1 Bioactive compounds containing the 1H-isochromene core structure

Scheme 1 Metal-catalyzed synthesis of 1H-isochromenes and the one-pot approach used in this work

Recently, our group has successfully combined gold/silver and organocatalysis for the one-pot synthesis of various annulated heterocycles.[10] In a continuation of this, we investigated the possibility of combining the silver-catalyzed formation of benzopyrylium cation intermediates with subsequent trapping by enolizable ketones under Brønsted acid catalysis.[11] For the synthesis of 1-substituted 1H-isochromenes, 2-alkynyl benzaldehydes were first synthesized by using a Sonoghashira coupling[12] of 2-bromo benzaldehydes and phenylacetylenes. For the initial optimization we chose 2-(2-phenylethynyl) benzaldehyde and one equivalent of acetylacetone as the nucleophile. A single-neck flask charged with the 2-alkynylbenzaldehyde dissolved in toluene, 2 mol% silvercarbonate as catalyst, and 10 mol% acetic acid was stirred for 24 hours, but these conditions gave no product (Table [1], entry 1). Further heating the reaction mixture at 60 °C overnight resulted only in some consumption of the 2-(2-phenylethynyl)benzaldehyde but did not lead to any desired product (entry 2).

Table 1 Optimization of the Reaction Conditions^a

Entry	Ag-Salt	Acid	T (°C)	t (h)	Solvent	Yield (%)b
1	Ag2CO3	AcOH	rt	24	toluene	nr
2	Ag2CO3	AcOH	60	24	toluene	nr
3	Ag2CO3	TFA	60	24	toluene	11
4	Ag2CO3	CF3SO3H	60	24	toluene	nr
5	Ag2CO3	DPP	60	24	toluene	42
6	Ag2CO3	DPP	60	22	CHCl3	15
7	Ag2CO3	DPP	60	22	EtOH	21
8	Ag2CO3	DPP	60	22	THF	34
9	Ag2CO3	DPP	40	24	n-hexane	66
10	Ag2CO3	–	40	24	n-hexane	nr
11	–	DPP	40	24	n-hexane	nr
12c	Ag2CO3	DPP	40	16	n-hexane	86
13	Ag2O	DPP	40	16	n-hexane	37
14	AgOTf	DPP	40	16	n-hexane	29
15	AgBF4	DPP	40	16	n-hexane	nr
16	AgNO3	DPP	40	16	n-hexane	nr
17d	Ag2CO3	DPP	40	16	n-hexane	93

^a Reaction conditions: 1a (0.4 mmol), 2a (0.4 mmol), acid (10 mol%), Ag₂CO₃ (0.008 mmol), n-hexane (0.3 M, 2.4 mL), 40 °C, 17 h.

^b Yield of isolated 3a after flash chromatography.

^c Acetyl acetone (2 equiv) used.

^d Compound 2a (0.8 mmol), Ag₂CO₃ (2.5 mol%) used and the concentration reduced to 0.17 M in n-hexane.

More Brønsted acids, for example trifluoroacetic acid (TFA), triflic acid and diphenyl phosphate (DPP), were screened (Table [1]). Whereas stronger acids such as triflic acid led to the decomposition of the substrate and no desired product formation, the use of TFA resulted in 11% of the 1H-isochromene product according to NMR spectroscopic analysis. Interestingly, the combination of 2 mol% silver carbonate and 10 mol% DPP led to an increased yield of 42% product. With this initial result in hand, a range of solvents were screened. n-Hexane turned out to be the best solvent for this reaction, resulting in 66% yield of the desired isochromene. When two equivalents of acetylacetone were used instead of one equivalent, the yield increased to 86%. The combination of DPP with different silver salts such as Ag₂O, AgOTf, AgBF₄ and AgNO₃ did not improve the yield.

It should be mentioned here that during the screening of conditions, we observed the formation of an intermediate that turned out to be the dimer of o-alkynylbenzaldehyde. This type of dimerization was previously reported by Yao and co-workers using a Brønsted acid.[13] The dimer formation was dependent on the concentration and the amount of the silver catalyst. Hence, further optimization of the reaction conditions was carried out. Finally, the optimal conditions were established as stirring o-alkynylbenzaldehyde with acetylacetone (0.17 M in n-hexane), Ag₂CO₃ (2.5 mol%) and DPP (10 mol%) at 40 °C for 16 h, leading to 93% yield of the desired 1H-isochromene 3a (Table [1], entry 17).

With the optimized conditions in hand, we tested a range of substituted o-alkynylbenzaldehydes as well as ketones as nucleophile such as phenyl acetone, 2-phenyl cyclohexanone, and methyl cyclopentanone-2-carboxylate. The easily enolizable acetylacetone (3b; Table [2]) resulted in a faster reaction and higher yield (97%) of the desired isochromene. Switching to the less enolizable nucleophile phenyl acetone (3c) required a longer reaction time and gave a lower yield of the product (54%) as a mixture of dia­stereomers.

Comparing the differently substituted aldehydes, no significant influence of the substituent groups was observed; substrates bearing electron-withdrawing (3d, 95%; Table [2]) or electron-donating substituents (3h, 91%), or both (3b, 97%), all gave similar yields.

Table 2 Synthesis of 1-Substituted 1H-Isochromenes 3a–l with Open-Chain Ketones as Nucleophiles^a

3	R1	R2	R4	R5	R6	R7	t (h)	Yield (%)b	d.r.c
3a	Me	COMe	H	H	H	H	16	93	–
3b	Me	COMe	H	F	Me	H	12	97	–
3c	Me	Ph	H	F	Me	H	23	54d	1.3:1
3d	Me	COMe	H	H	H	F	13	95	–
3e	Me	Ph	H	H	H	F	23	50d	1.4:1
3f	Me	COMe	OMe	H	H	H	18	92	–
3g	Me	Ph	OMe	H	H	H	19	16d	3:1
3h	Me	COMe	H	H	t-Bu	H	16	91	–
3i	Me	Ph	H	H	t-Bu	H	19	54d	1.1:1
3j	Me	COMe	H	H	OMe	H	18	91	–
3k	Me	Ph	H	H	OMe	H	23	52d	1.1:1
3l	Me	Ph	H	Cl	H	H	68	65d	1.3:1

^a Reaction conditions: 1 (0.4 mmol), 2 (0.8 mmol), DPP (10 mol%), Ag₂CO₃ (2.5 mol%), n-hexane (0.17 M), 40 °C.

^b Yield of the isolated product after flash chromatography.

^c Based on ¹H NMR spectroscopic analysis.

^d Compound 1 (0.3 mmol) and 2 (0.9 mmol) used in n-hexane (0.17 M, 1.8 mL).

There was an influence of the substituents at the aldehyde when 2-phenylcyclohexanone was used as ketone nucleophile. When the aldehyde was substituted at the R⁴ position with an electron-donating methoxy group, the d.r. was in the range of 1:1 (3v; Table [3]), but when the substituent was on R⁶, the d.r. increased to 9:1 (3z). Furthermore, the yields obtained for 3o–q clearly show the impact of the activation of the different nucleophiles. Methyl cyclopentanone-2-carboxylate and 2-acetylcyclopentanone, being 1,3-dicarbonyl compounds, are much more enolizable, leading to 1H-isochromene 3o (96% yield) and 3q (74% yield) in excellent or good yields, respectively. In comparison, 2-phenylcyclohexan-1-one, which is a cyclic ketone containing a sterically demanding phenyl substituent, is not easily enolizable and its use led to moderate yield and required a longer reaction time (3p; 59%, 23 h).

Table 3 Synthesis of 1-Substituted 1H-Isochromenes 3m–a′ with Cyclic Ketones as Nucleophiles^a

3	R1–R3	R2	R4	R5	R6	R7	t (h)	Yield (%)b	d.r.c
3m	-(CH2)3-	CO2Me	H	H	H	H	16	90	1.5:1
3n	-(CH2)4-	Ph	H	H	H	H	16	40d	2.7:1
3o	-(CH2)3-	CO2Me	H	F	Me	H	16	96	1:1
3p	-(CH2)4-	Ph	H	F	Me	H	23	59d	2:1
3q	-(CH2)3-	COMe	H	F	Me	H	16	74	1.4:1
3r	-(CH2)3-	CO2Et	H	F	Me	H	36	82	1.7:1
3s	-(CH2)3-	CO2Me	H	H	H	F	16	93	1.7:1
3t	-(CH2)4-	Ph	H	H	H	F	23	66d	2:1
3u	-(CH2)3-	CO2Me	OMe	H	H	H	16	91	1.2:1
3v	-(CH2)4-	Ph	OMe	H	H	H	19	37d	1:1
3w	-(CH2)3-	CO2Me	H	H	t-Bu	H	16	90	1.1:1
3x	-(CH2)4-	Ph	H	H	t-Bu	H	19	54d	2.2:1
3y	-(CH2)3-	CO2Me	H	H	OMe	H	16	92	1.5:1
3z	-(CH2)4-	Ph	H	H	OMe	H	23	52d	9:1
3a′	-(CH2)3-	CO2Me	H	Cl	H	H	46	92	1.1:1

^a Reaction conditions: 1 (0.4 mmol), 2 (0.8 mmol), DPP (10 mol%), Ag₂CO₃ (2.5 mol%), n-hexane (0.17 M), 40 °C.

^b Yield of the isolated product after flash chromatography.

^c Based on ¹H NMR spectroscopic analysis.

^d Compound 1 (0.3 mmol), 2 (0.9 mmol), DPP (10 mol%), Ag₂CO₃ (2.5 mol%), n-hexane (0.17 M, 1.8 mL), 40 °C.

It is well known that under silver-catalyzed cyclization either a 5-exo-dig or a 6-endo-dig ring system can be generated. To confirm the relative configuration of the 1H-isochromenes and to evaluate whether a five- or a six-membered ring is formed, the major diastereomer of 3p was separated by preparative HPLC. Subsequent HMBC NMR experiments with the purified diastereomer of 3p were carried out, but the results were inconclusive. The proposed structure including the relative configuration was finally determined by X-ray crystal structure analysis of compound rac-3p. It was thereby confirmed that a six-membered isochromene ring system was formed (Figure [2]).

Figure 2 X-ray crystal structure of rac-3p [14]

Scheme 2 Enantioselective synthesis of 1H-isochromene 3n (absolute configuration not determined)

Having successfully developed a one-pot synthesis of 1H-isochromenes, we focused on an enantioselective version of our method. To date, there have been only a few enantioselective protocols to synthesize enantioenriched 1H-isochromenes. Terada and co-workers have reported an enantioselective cyclization/reduction cascade by using a chiral Ag-catalyst.[15] Recently, Uemura and co-workers reported a chiral Au-complex catalyzed desymmetrization of 2-alkynylbenzaldehydes.[16] Most recently, Ghorai and co-workers reported an enantioselective synthesis of 1H-isochromenes through intramolecular oxa-Michael addition by using a chiral bifunctional organocatalyst.[17] In the past years, chiral phosphoric acid catalysis has been developed as an extremely powerful tool in many asymmetric transformations, both under homogeneous[18] and heterogeneous conditions.[19] At present, the combination of chiral phosphoric acids with metal catalysts is of particular interest.[20]

We envisioned that the use of a chiral phosphoric acid instead of the achiral diphenyl phosphate may lead to enantioenriched 1H-isochromenes. Stirring 2-phenyl cyclohexan-1-one with substrate 1a in the presence of 2.5 mol% Ag₂CO_3­ and 10% (R)-TRIP catalyst at 40 °C for 30 minutes and then stirring at 0 °C for 3 days yielded 33% isolated product with a d.r. of 2.3:1 and 63% ee of the major diastereomer (Scheme [2]). Further development and optimization of this enantioselective version is under investigation in our research group.

In conclusion, we have developed a new one-pot protocol for the synthesis of 1-substituted 1H-isochromenes involving 2-alkynyl benzaldehydes and ketone nucleophiles, such as open-chain 1,3-diketones, phenylacetone, cyclic β-ketoesters, and 2-phenyl cyclohexanone, as substrates. This one-pot method combines transition-metal catalysis with organocatalytic Brønsted acid catalysis. The possibility of an enantioselective version has also been successfully tested.

All reactions were performed in oven-dried glassware. Starting materials and reagents were purchased from commercial suppliers (ABCR, Acros, Sigma Aldrich and TCI Europe), which were used without further purification unless otherwise noted. All solvents were distilled, purified, and dried according to standard procedures. Analytical TLC was performed by using SIL G-25 UV254 from Machery & Nagel (particle size 0.040–0.063 nm; 230–240 mesh, flash) and visualized with ultraviolet radiation at 254 nm. ¹H, ¹³C, and ¹⁹F NMR spectra were recorded with a Varian Inova 600 instrument with deuterated chloroform, benzene or acetonitrile as solvents depending on the solubility and sensitivity of the compounds. Chemical shifts for ¹H, ¹³C and ¹⁹F NMR spectra are reported in parts per million (ppm), with coupling constants given in Hertz (Hz). Standard abbreviations are used to denote spin multiplicities. Mass spectra were recorded with a SSQ7000 spectrometer from Finnigan at 70 eV. HRMS data (ESI) were collected with a ThermoFisher Sientific LTQ-Orbitrap XL apparatus. IR spectra were recorded with a Perkin Elmer Spectrum 100 FTIR spectrophotometer. Analytical HPLC was carried out either with a Hewlett-Packard­ 1050 series instrument or a Agilent 1100 instrument using a chiral stationary phase (Diacel Chiralpak IC, IA, AD, AS and IB columns). Preparative HPLC was carried out with a Knauer Azura System. Optical rotation values were measured with a Perkin Elmer 241 polarimeter and melting points were obtained with a LLG MPM-H2 apparatus.

1H-Isochromenes 3; General Procedure

A dry single-necked flask was charged with 2-alkynylaldehyde 1 (0.4 mmol, 1 equiv), ketone 2 (0.8 mmol, 2 equiv), and diphenylphosphate (10 mg, 0.04 mmol, 10 mol %) in hexane (2.4 mL), and silver carbonate (2.75 mg 0.01 mmol, 2.5 mol%) was added. The mixture was heated to 40 °C and stirred until the 2-alkynylaldehyde was completely consumed (progress of the reaction was monitored by TLC). The hexane was evaporated and the mixture was diluted in EtOAc (50 mL) and washed three times with water. The organic layer was dried over anhydrous Na₂SO₄ and filtered. After evaporating the EtOAc, the crude product was dissolved in dichloromethane and purified by column chromatography (silica gel; pentane/EtOAc, 96:4) to give pure 1H-isochromenes 3 as yellow oils or as colorless solids. In the case of phenyl­acetone and 2-phenylcyclohexanone as ketone nucleophiles, the crude product was directly purified by flash chromatography on silica gel.

3-(3-Phenyl-1H-isochromen-1-yl)pentane-2,4-dione (3a)

Yield: 112 mg (93%); colorless solid; mp 129–131 °C; R_f = 0.5 (n-pentane/EtOAc, 10:1); keto/enol = 1:1.3.

IR (ATR): 3741, 3456, 3266, 3006, 2424, 2180, 2061, 1898, 1732, 1361, 1218, 1054, 924, 839, 760, 691 cm⁻¹.

¹H NMR (600 MHz, CDCl₃): δ (keto) = 7.59 (d, J = 6.9 Hz, 2 H), 7.40 (t, J = 6.7 Hz, 2 H), 7.39–7.33 (m, 2 H), 7.28 (t, J = 6.2 Hz, 1 H), 7.13 (d, J = 7.5 Hz, 2 H), 7.02 (d, J = 7.9 Hz, 1 H), 6.51 (s, 1 H), 6.15 (d, J = 10.4 Hz, 1 H), 4.65 (d, J = 10.4 Hz, 1 H), 2.37 (s, 3 H), 1.90 (s, 3 H).

¹H NMR (600 MHz, CDCl₃): δ (enol) = 17.52 (s, 1 H), 7.73 (d, J = 7.1 Hz, 2 H), 7.39–7.33 (m, 2 H), 7.27–7.24 (m, 1 H), 7.16 (ddd, J = 7.6, 3.4, 1.1 Hz, 2 H), 6.94 (d, J = 7.5 Hz, 1 H), 6.47 (s, 1 H), 6.25 (s, 1 H), 2.21 (s, 3 H), 2.12 (s, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ (keto/enol mixture) = 201.2 (C_q), 200.9 (C_q), 153.7 (C_q), 150.6 (C_q), 133.9 (C_q), 133.5 (C_q), 132.5 (C_q), 130.5 (C_q), 130.3 (C_q), 129.2 (CH_Ar), 129.0 (CH_Ar), 128.9 (CH_Ar), 128.5 (CH_Ar), 128.5 (2C, CH_Ar), 128.4 (2C, CH_Ar),127.3 (C_q), 127.0 (CH_Ar), 126.8 (CH_Ar), 125.1 (CH_Ar), 124.9 (2C, CH_Ar), 124.8 (2C, CH_Ar), 124.5 (CH_Ar), 124.1 (CH_Ar), 123.5 (CH_Ar), 109.1 (C_q), 100.7 (CH), 100.6 (CH), 76.5 (CH), 76.3 (CH), 70.7 (CH), 32.1 (CH₃), 29.0 (CH₃).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₁₈O₃Na: 329.1148; found: 329.1146.

3-(6-Fluoro-3-p-tolyl-1H-isochromen-1-yl)pentane-2,4-dione (3b)

Yield: 131 mg (97%); pale-yellow solid; mp 116–118 °C; R_f = 0.54 (n-pentane/EtOAc, 10:1).

IR (ATR): 3426, 3048, 2969, 2926, 2658, 2325, 2097, 1917, 1677, 1621, 1497, 1427, 1382, 1306, 1213, 1135, 1020, 935, 908, 825 (s), 781, 730, 663 cm⁻¹.

¹H NMR (600 MHz, CDCl₃): δ = 7.95 (d, J = 8.2 Hz, 2 H), 7.43 (s, 1 H), 7.37 (dd, J = 8.4, 5.6 Hz, 1 H), 7.28 (d, J = 8.2 Hz, 2 H), 6.99 (td, J = 8.4, 2.5 Hz, 1 H), 6.78 (dd, J = 8.7, 2.5 Hz, 1 H), 5.59 (s, 1 H), 4.88 (s, 1 H), 2.48 (s, 3 H), 2.42 (s, 3 H), 1.53 (s, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 201.6 (Cq), 196.5 (Cq), 163.7 (d, J = 219 Hz, CF), 144.0 (C_q), 138.4 (C_q), 138.0 (CH), 137.5 (C_q), 135.4 (C_q), 131.6 (d, J = 4.5 Hz, CH_Ar), 129.2 (CH_Ar, 2C), 129.2 (CH_Ar, 2C), 128.6 (C_q), 116.07 (d, J = 10.6 Hz, CH_Ar), 115.1 (d, J = 10.6 Hz, CH_Ar), 75.7 (C_q), 56.3 (CH), 29.6 (CH₃), 26.3 (CH₃), 21.6 (CH₃).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₁H₁₉O₃FNa: 361.1210; found: 361.1211.

1-(6-Fluoro-3-p-tolyl-1H-isochromen-1-yl)-1-phenylpropan-2-one (3c)

Yield: 61 mg (54%); colorless solid; mp 125 °C; R_f = 0.6 (n-pentane/EtOAc, 10:1); dr = 1.3:1.

IR (ATR): 3860, 3424, 3017, 2661, 2317, 2087, 1892, 1714, 1606, 1470, 1371, 1241, 1138, 1050, 966, 789 cm⁻¹.

¹H NMR (600 MHz, CDCl₃): δ = 7.58 (d, J = 1.9 Hz, 1 H), 7.34–7.30 (m, 3 H), 7.24–7.19 (m, 2 H), 6.97–6.94 (m, 2 H), 6.89–6.86 (m, 2 H), 6.85–6.81 (m, 1 H), 6.76 (dd, J = 9.4, 2.6 Hz, 1 H), 6.39 (s, 1 H), 6.06 (d, J = 10.3 Hz, 1 H), 4.46 (d, J = 2.3 Hz, 1 H), 2.30 (s, 3 H), 1.89 (s, 3 H).

¹H NMR (600 MHz, CDCl₃): δ = 7.59 (d, J = 1.9 Hz, 1 H), 7.37 (d, J = 2.7 Hz, 1 H), 7.34–7.30 (m, 2 H), 7.24–7.19 (m, 2 H), 7.18–7.15 (m, 1 H), 7.00–6.97 (m, 2 H), 6.85–6.81 (m, 1 H), 6.44 (s, 1 H), 6.41 (dd, J = 8.5, 2.5, 1 H), 6.05–6.03 (m, 1 H), 5.98 (d, J = 10.3 Hz, 1 H), 4.45 (d, J = 2.5 Hz, 1 H), 2.39 (s, 3 H), 2.07 (s, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 206.5, 152.55, 151.4, 139.4, 135.0, 133.6, 131.0, 130.5, 129.5, 129.35, 129.1, 128.8, 128.1, 127.9, 125.65, 125.15, 112.9, 112.7, 112.1, 111.9, 99.1, 78.55, 61.8, 31.3, 21.4.

¹³C NMR (151 MHz, CDCl₃): δ = 206.5, 163.8, 162.0, 139.6, 134.6, 130.5, 128.4, 128.1, 127.9, 127.8, 127.7, 127.4, 127.4, 125.6, 123.4, 110.6, 110.4, 110.25, 110.1, 99.0, 78.55, 61.8, 59.5, 31.3, 21.5.

¹⁹F NMR (564 MHz, CDCl₃): δ = −114.35 (major), −114.59 (minor).

HRMS (ESI): m/z [M⁺] calcd for C₂₅H₂₁O₂F: 372.1520; found: 372.1526.

3-[3-(3-Fluorophenyl)-1H-isochromen-1-yl]pentane-2,4-dione (3d)

Yield: 123 mg (95%); yellow solid; mp 122–124 °C; R_f = 0.48 (n-pentane/EtOAc, 10:1).

IR (ATR): 3403, 3173, 3074, 2976, 2881, 2662, 2330, 2207, 2087, 2002, 1924, 1855, 1729, 1700, 1609, 1583, 1485, 1445, 1359, 1267, 1216, 1158, 1051, 951, 873, 784, 754, 688 cm⁻¹.

¹H NMR (600 MHz, CDCl₃): δ (enol) = 17.52 (s, 1 H), 7.52–7.49 (m, 1 H), 7.42–7.24 (m, 4 H), 7.13 (d, J = 7.5 Hz, 1 H), 7.03 (m, 2 H), 6.47 (s, 1 H), 6.26 (s, 1 H), 2.17–2.08 (6 H).

¹H NMR (600 MHz, CDCl₃): δ (keto) = 7.43–7.24 (m, 4 H), 7.19–7.14 (m, 3 H), 6.95 (d, J = 7.5 Hz, 1 H), 6.51 (s, 1 H), 6.14 (d, J = 10.4 Hz, 1 H), 4.61 (d, J = 10.4 Hz, 1 H), 2.37 (s, 3 H), 1.90 (s, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ (keto form only) = 201.1 (C=O), 200.7 (C=O), 162.9 (d, J = 244.6 Hz, CF), 151.3 (C_q), 149.3 (C_q), 136.1 (dd, J = 64.9, 9 Hz, C_q), 132.0 (C_q), 130.0 (CH_Ar), 128.8 (CH_Ar), 127.3 (CH_Ar), 125.0 (CH_Ar), 123.9 (CH_Ar), 120.4 (CH_Ar), 115.8 (CH_Ar), 111.7 (CH_Ar), 101.68 (CH), 76.5 (CH), 70.91 (CH), 32.1 (CH), 28.8 (CH).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₁₇O₃FNa: 347.1054; found: 347.1057.

1-[3-(3-Fluorophenyl)-1H-isochromen-1-yl]-1-phenylpropan-2-one (3e)

Yield: 54 mg (50 %); yellow solid; mp 123 °C; R_f = 0.43 (n-pentane/EtOAc, 10:1); dr = 1.4:1.

IR (ATR): 3403, 3048, 2933, 2672, 2319, 2091, 1900, 1705, 1587, 1458, 1351, 1275, 1160, 1055, 895, 773 cm⁻¹.

¹H NMR (600 MHz, CD₃CN): δ (major) = 7.52 (m, 1 H), 7.41–7.37 (m, 1 H), 7.36–7.30 (m, 2 H), 7.25–7.19 (m, 3 H), 7.17–7.14 (m, 2 H), 7.07–7.05 (m, 2 H), 6.79 (d, J = 7.7 Hz, 1 H), 6.75 (s, 1 H), 6.29–6.26 (m, 1 H), 6.04 (d, J = 10.3 Hz, 1 H), 4.56 (d, J = 8.8 Hz, 1 H), 2.02 (s, 3 H).

¹H NMR (600 MHz, CD₃CN): δ (minor) = 7.53–7.52 (m, 1 H), 7.45 (td, J = 8.0, 5.9 Hz, 1 H), 7.36–7.30 (m, 2 H), 7.25–7.19 (m, 3 H), 7.17–7.14 (m, 2 H), 7.12 (dd, J = 8.6, 2.7 Hz, 1 H), 7.02 (d, J = 7.9 Hz, 1 H), 6.98 (t, J = 8.4 Hz, 1 H), 6.68 (s, 1 H), 6.57 (d, J = 10.9 Hz, 1 H), 6.08 (d, J = 10.2 Hz, 1 H), 4.56 (d, J = 10.2 Hz, 1 H), 1.85 (s, 3 H).

¹³C NMR (151 MHz, CD₃CN): δ (major) = 207.1, 134.9, 131.4, 131.1, 130.7, 130.1, 129.6, 129.2, 128.8, 126.9, 126.5, 125.5, 125.0, 121.5, 116.6, 116.5, 112.35, 112.2, 103.0, 79.8, 78.1, 62.25, 60.3, 31.0.

¹³C NMR (151 MHz, CD₃CN): δ (minor) = 207.1, 136.45, 131.5, 131.1, 130.7, 130.2, 129.65, 129.5, 128.6, 127.8, 126.8, 121.7, 121.6, 121.5, 116.2, 116.1, 112.7, 112.6, 103.0, 79.2, 78.1, 62.25, 60.3, 30.7.

¹⁹F NMR (564 MHz, CDCl₃): δ = −114.51 (major), −115.07 (minor).

HRMS (ESI): m/z [M⁺] calcd for C₂₄H₁₉O₂F: 358.1364; found: 358.1368.

3-(7-Methoxy-3-phenyl-1H-isochromen-1-yl)pentane-2,4-dione (3f)

Yield: 127 (92%); yellow oil; R_f = 0.4 (n-pentane/EtOAc, 10:1).

IR (ATR): 3442, 2944, 2322, 2085, 1911, 1716, 1598, 1474, 1257, 1150, 1034, 842, 759, 693 cm⁻¹.

¹H NMR (600 MHz, CDCl₃): δ = 7.56 (d, J = 7.2 Hz, 2 H), 7.35 (t, J = 7.4 Hz, 2 H), 7.30 (t, J = 7.3 Hz, 1 H), 7.08 (d, J = 8.4 Hz, 1 H), 6.82 (dd, J = 8.3, 2.6 Hz, 1 H), 6.60 (d, J = 2.6 Hz, 1 H), 6.47 (s, 1 H), 6.09 (d, J = 10.3 Hz, 1 H), 4.62 (d, J = 10.3 Hz, 1 H), 3.78 (s, 3 H), 2.35 (s, 3 H), 1.92 (s, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ = 201.2 (CH₃C=O, C_q), 200.8 (CH₃C=O, C_q), 158.7 (C_q), 148.6 (C_q), 133.7 (C_q), 129.0 (C_q), 128.7 (CH_Ar), 128.4 (CH_Ar, 2C), 125.8 (CH_Ar), 124.4 (CH_Ar, 2C), 123.1 (C_q), 114.5 (CH_Ar), 110.9 (CH_Ar), 100.4 (CH), 76.5 (CH), 70.7 (CH), 55.4 (OCH₃), 32.1 (CH₃), 29.1 (CH₃).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₁H₂₀O₄Na: 359.1254; found: 359.1251.

1-(7-Methoxy-3-phenyl-1H-isochromen-1-yl)-1-phenylpropan-2-one (3g)

Yield: 17 mg (16 %); yellow oil; R_f = 0.46 (n-pentane/Et₂O, 6:2); dr = 3:1.

IR (ATR): 3794, 3455, 2971, 2180, 2041, 1740, 1588, 1367, 1218, 931, 833, 697 cm⁻¹.

¹H NMR (600 MHz, benzene-d ₆): δ (major) = 7.82–7.79 (m, 2 H), 7.11–7.02 (m, 3 H), 6.93–6.90 (m, 3 H), 6.89–6.87 (m, 3 H), 6.71 (dd, J = 8.3, 2.6 Hz, 1 H), 6.47 (s, 1 H), 6.18 (d, J = 10.2 Hz, 1 H), 5.58 (d, J = 2.5 Hz, 1 H), 4.43 (d, J = 10.3 Hz, 1 H), 3.00 (s, 3 H), 1.73 (s, 3 H).

¹H NMR (600 MHz, benzene-d ₆): δ (minor) = 7.24–7.22 (m, 2 H), 7.11–7.02 (m, 3 H), 7.01–6.94 (m, 4 H), 6.89–6.87 (m, 3 H), 6.84–6.82 (m, 1 H), 6.48 (s, 1 H), 6.27 (d, J = 10.5 Hz, 1 H), 4.39 (d, J = 15.1 Hz, 1 H), 3.38 (s, 3 H), 1.42 (s, 3 H).

¹³C NMR (151 MHz, benzene-d ₆): δ (major) = 205.0, 158.4, 148.7, 135.0, 134.4, 130.25, 129.6, 129.1 (2C), 128.8 (2C), 127.7, 127.1, 125.8, 125.3 (2C), 125.0 (2C), 115.2, 111.2, 100.6, 79.6, 59.9, 54.7, 30.8.

¹³C NMR (151 MHz, benzene-d ₆): δ (minor) = 205.4, 159.2, 149.7, 135.9, 134.5, 131.1, 129.65 (2C), 129.1 (2C), 128.8, 128.5, 127.4, 126.0, 125.4 (2C), 123.8 (2C), 114.85, 112.1, 100.6, 78.0, 62.3, 55.0, 30.4.

HRMS (ESI): m/z [M⁺] calcd for C₂₅H₂₂O₃: 370.1563; found: 370.1565.

3-[3-(4-tert-Butylphenyl)-1H-isochromen-1-yl]pentane-2,4-dione (3h)

Yield: 131 mg (91%); colorless solid; mp 108–110 °C; R_f = 0.55 (n-pentane/EtOAc, 10:1).

IR (ATR): 3912, 3779, 2959, 2646, 2321, 2177, 2062, 1992, 1921, 1714, 1603, 1406, 1361, 1265, 1208, 1110, 1044, 926, 814, 749, 698 cm⁻¹.

¹H NMR (600 MHz, CDCl₃): δ (enol) = 17.51 (s, 1 H), 7.67 (d, J = 8.4 Hz, 2 H), 7.42 (d, J = 8.4 Hz, 2 H), 7.24 (d, J = 7.5 Hz, 1 H), 7.15–7.12 (m, 2 H), 6.93 (d, J = 7.5 Hz, 1 H), 6.43 (s, 1 H), 6.22 (s, 1 H), 2.22 (s, 3 H), 2.10 (s, 3 H), 1.34 (s, 9 H).

¹H NMR (600 MHz, CDCl₃): δ (keto) = 7.51 (d, J = 8.5 Hz, 2 H), 7.39 (d, J = 8.4 Hz, 2 H), 7.29–7.26 (m, 1 H), 7.12 (d, J = 7.7 Hz, 2 H), 7.01 (d, J = 7.5 Hz, 1 H), 6.46 (s, 1 H), 6.13 (d, J = 10.3 Hz, 1 H), 4.63 (d, J = 10.4 Hz, 1 H), 2.39 (s, 3 H), 1.89 (s, 3 H), 1.32 (s, 9 H).

¹³C NMR (151 MHz, CDCl₃): δ (keto/enol mixture) = 201.3 (C=O), 201.0 (C=O), 153.8 (C_q), 152.4 (Cq), 150.8 (C_q), 132.7 (C_q), 131.1 (C_q), 130.6 (C_q), 130.45 (C_q), 128.9 (CH_Ar), 128.4 (CH_Ar), 127.2 (C_q), 126.75 (CH_Ar), 126.6 (CH_Ar), 125.4 (CH_Ar), 125.35 (2C, CH_Ar), 125.1 (C_q), 124.7 (2C, CH_Ar), 124.65 (CH_Ar), 124.3 (CH_Ar), 123.9 (CH_Ar), 123.45 (CH_Ar), 109.1 (C_q), 100.1 (CH), 99.95 (CH), 76.5 (CH), 76.2 (CH), 70.7 (CH), 34.7 (C_q), 32.15 (CH₃), 31.2 (3C, CH₃),31.2 (3C, CH₃), 28.9 (CH₃).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₂₆O₃Na: 385.1774; found: 385.1171.

1-{3-[4-(tert-Butyl)phenyl]-1H-isochromen-1-yl}-1-phenylpropan-2-one (3i)

Yield: 64 mg (54 %); pale-yellow solid; mp 134 °C; R_f = 0.54 (n-pentane/EtOAc, 15:1); dr = 1.1:1.

IR (ATR): 3819, 3402, 3029, 2958, 2323, 2101, 2002, 1919, 1709, 1614, 1484, 1410, 1357, 1269, 1205, 1155, 1114, 1060, 928, 809, 748, 695 cm⁻¹.

¹H NMR (600 MHz, CD₃CN): δ (major) = 7.37–7.28 (m, 5 H), 7.24–7.17 (m, 2 H), 7.14–7.12 (m, 2 H), 7.00–6.97 (m, 2 H), 6.75 (dt, J = 7.5, 4.2 Hz, 1 H), 6.58 (s, 1 H), 6.27 (dt, J = 7.5, 0.8 Hz, 1 H), 6.06 (d, J = 10.1 Hz, 1 H), 4.60 (d, J = 10.1 Hz, 1 H), 1.85 (s, 3 H), 1.26 (s, 9 H).

¹H NMR (600 MHz, CD₃CN): δ (minor) = 7.63–7.60 (m, 2 H), 7.50–7.47 (m, 2 H), 7.37–7.28 (m, 2 H), 7.24–7.17 (m, 4 H), 7.14–7.12 (m, 1 H), 7.08–7.05 (m, 2 H), 6.66 (s, 1 H), 6.03 (dd, J = 10.4, 0.6 Hz, 1 H), 4.57 (d, J = 10.4 Hz, 1 H), 2.03 (s, 3 H), 1.33 (s, 9 H).

¹³C NMR (151 MHz, CD₃CN): δ (major) = 207.2, 153.1, 152.0, 136.6, 135.0, 132.0, 130.6, 130.2 (2 C), 129.6, 129.4, 129.1, 128.5, 127.15, 126.7, 126.5, 125.9, 125.5, 125.0 (2 C), 101.0, 78.1, 62.0, 35.2, 31.3 (3C), 31.0.

¹³C NMR (151 MHz, CD₃CN): δ (minor) = 207.2, 153.2, 150.9, 132.4, 131.9, 131.6, 130.6, 130.1 (2C), 129.5, 129.4, 128.9, 128.7, 126.8, 126.5, 126.3, 125.9, 125.5, 124.6 (2C), 101.1, 79.1, 60.2, 35.3, 31.4 (3C), 30.8.

HRMS (ESI): m/z [M⁺] calcd for C₂₈H₂₈O₂: 396.2084; found: 396.2086.

3-[3-(4-Methoxyphenyl)-1H-isochromen-1-yl]pentane-2,4-dione (3j)

Yield: 122 mg (91%); colorless solid; mp 137.5–138.5 °C; R_f = 0.45 (n-pentane/EtOAc, 10:1).

IR (ATR): 3854, 3395, 2941, 2646, 2332, 2095, 1921, 1718, 1598, 1479, 1369, 1253, 1165, 1025, 932, 789 cm⁻¹.

¹H NMR (600 MHz, CDCl₃): δ (enol) = 17.51 (s, 1 H), 7.69–7.65 (m, 2 H), 7.25–7.23 (m, 1 H), 7.14–7.11 (m, 2 H), 6.93 (s, 1 H), 6.91 (d, J = 6.9 Hz, 2 H), 6.35 (s, 1 H), 6.21 (s, 1 H), 3.84 (s, 3 H), 2.22 (s, 3 H), 2.10 (s, 3 H).

¹H NMR (600 MHz, CDCl₃): δ (keto) = 7.53–7.51 (m, 2 H), 7.26 (t, J = 1.9 Hz, 1 H), 7.11–7.08 (m, 2 H), 7.00 (d, J = 7.7 Hz, 1 H), 6.90–6.88 (m, 2 H), 6.39 (s, 1 H), 6.12 (d, J = 10.4 Hz, 1 H), 4.64 (d, J = 10.3 Hz, 1 H), 3.82 (s, 3 H), 2.37 (s, 3 H), 1.89 (s, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ (keto/enol mixture) = 201.2 (C_q), 201.0 (C_q), 160.4 (C_q), 153.7 (C_q), 150.6 (C_q), 132.8 (C_q), 130.7 (C_q), 130.2 (C_q), 128.9 (CH_Ar), 128.4 (CH_Ar), 127.0 (C_q), 126.5 (2C, CH_Ar), 126.4 (2C, CH_Ar), 126.1 (C_q), 125.1 (CH_Ar), 124.15 (CH_Ar), 123.7 (CH_Ar), 123.4 (CH_Ar), 113.9 (2C, CH_Ar), 113.8 (2C, CH_Ar), 109.1 (C_q), 99.1 (CH), 99.0 (CH), 76.6 (CH), 76.25 (CH), 70.6 (CH), 55.3 (OCH₃), 32.1 (CH₃), 29.05 (CH₃).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₁H₂₀O₄Na: 359.1254; found: 359.1252.

1-[3-(4-Methoxyphenyl)-1H-isochromen-1-yl]-1-phenylpropan-2-one(3k)

Yield: 58 mg (52%); colorless solid; mp 120 °C; R_f = 0.49 (n-pentane/Et₂O, 7:2); dr = 1.1:1.

IR (ATR): 3829, 3472, 3177, 3041, 2646, 2301, 2088, 1905, 1746, 1634, 1493, 1245, 1008, 887, 747 cm⁻¹.

¹H NMR (600 MHz, CD₃CN): δ (major) = 7.50–7.48 (m, 2 H), 7.46–7.43 (m, 2 H), 7.34–7.31 (m, 4 H), 7.28–7.26 (m, 2 H), 7.21–7.16 (m, 1 H), 6.93–6.91 (m, 2 H), 4.74 (d, J = 4.3 Hz, 1 H), 4.38 (d, J = 10.5 Hz, 1 H), 4.17 (s, 1 H), 3.80 (s, 3 H), 2.12 (s, 3 H).

¹H NMR (600 MHz, CD₃CN): δ (minor) = 7.96–7.93 (m, 1 H), 7.54–7.52 (m, 2 H), 7.39–7.36 (m, 1 H), 7.34–7.31 (m, 1 H), 7.26–7.24 (m, 1 H), 7.21–7.16 (m, 4 H), 7.14–6.95 (m, 2 H), 6.91–6.89 (m, 1 H), 6.3 (d, J = 4.3 Hz, 1 H), 5.29 (d, J = 4.3 Hz, 1 H), 4.29 (s, 1 H), 3.74 (s, 3 H), 2.04 (s, 3 H).

¹³C NMR (151 MHz, CD₃CN): δ (major) = 209.3, 187.3, 160.2, 137.4, 136.4, 136.3, 132.4, 130.9 (2C), 130.6, 129.6 (2C), 129.3, 128.6 (2C), 127.8, 127.6, 124.6, 114.7, 113.8 (2C), 71.9, 55.8, 50.7, 31.0.

¹³C NMR (151 MHz, CD₃CN): δ (minor) = 207.0, 187.3, 160.2, 137.4, 136.7, 136.1, 132.4, 130.8 (2C), 129.9, 129.5 (2C), 129.0, 128.7 (2C), 128.6, 128.2, 124.6, 114.6, 113.8 (2C), 79.0, 74.0, 64.0, 29.7.

HRMS (ESI): m/z [M⁺] calcd for C₂₅H₂₂O₃: 370.1563; found: 370.1565.

1-(6-Chloro-3-phenyl-1H-isochromen-1-yl)-1-phenylpropan-2-one (3l)

Yield: 73 mg (65%); pale-yellow solid; mp 125 °C; R_f = 0.72 (n-pentane/EtOAc, 10:1); dr = 1.3:1.

IR (ATR): 3437, 2954, 2669, 2339, 2096, 1898, 1721, 1601, 1456, 1361, 1247, 1055, 908, 701 cm⁻¹.

¹H NMR (600 MHz, CD₃CN): δ (major) = 7.70 (t, J = 1.3 Hz, 1 H), 7.46 (m, 2 H), 7.36–7.33 (m, 2 H), 7.30–7.24 (m, 2 H), 7.22–7.16 (m, 2 H), 7.10–7.05 (m, 2 H), 6.77 (dd, J = 8.1, 2.1 Hz, 1 H), 6.68 (s, 1 H), 6.24 (d, J = 8.0 Hz, 1 H), 6.08 (d, J = 10.3 Hz, 1 H), 4.59 (s, 1 H), 2.16 (d, J = 0.8 Hz, 3 H).

¹H NMR (600 MHz, CD₃CN): δ (minor) = 7.72 (d, J = 1.8 Hz, 1 H), 7.46 (m, 2 H), 7.36–7.33 (m, 2 H), 7.30–7.24 (m, 2 H), 7.22–7.16 (m, 2 H), 7.10–7.05 (m, 2 H), 6.77 (dd, J = 8.1, 2.1 Hz, 1 H), 6.61 (s, 1 H), 6.24 (d, J = 8.0 Hz, 1 H), 6.12 (d, J = 10.1 Hz, 1 H), 4.58 (d, J = 1.2 Hz, 1 H), 2.04 (s, 3 H).

¹³C NMR (151 MHz, CD₃CN): δ (major) = 206.9, 152.0, 136.2, 134.6, 134.2, 133.6, 130.4, 130.1 (2C), 129.7 (2C), 129.0 (2C), 128.9 (2C), 127.5, 126.8, 125.9 (2C), 124.2, 100.6, 78.7, 59.9, 30.8.

¹³C NMR (151 MHz, CD₃CN): δ (minor) = 207.0, 153.1, 134.7, 134.5, 134.2, 133.9, 130.2, 130.2 (2C), 129.6 (2C), 129.3 (2C), 128.6 (2C), 128.3, 126.2, 126.0 (2C), 124.5, 100.6, 77.6, 62.0, 30.8.

HRMS (ESI): m/z [M⁺] calcd for C₂₄H₁₉O₂Cl: 374.1068; found: 374.1069.

Methyl 2-Oxo-1-(3-phenyl-1H-isochromen-1-yl)cyclopentanecarboxylate (3m)

Yield: 125 mg (90%); colorless solid; mp 128.5–130.5 °C; R_f = 0.5 (n-pentane/EtOAc, 85:15); dr = 1.5:1.

IR (ATR): 3839, 3457, 2968, 2324, 2083, 1735, 1450, 1368, 1221, 1074, 929, 764, 691 cm⁻¹.

¹H NMR (600 MHz, CDCl₃): δ (major) = 7.61–7.57 (m, 2 H), 7.39–7.32 (m, 3 H), 7.28–7.23 (m, 2 H), 7.16–7.09 (m, 1 H), 6.97–6.93 (m, 1 H), 6.43 (s, 1 H), 6.29 (s, 1 H), 3.89 (s, 3 H), 2.72–2.67 (m, 1 H), 2.45–2.38 (m, 1 H), 2.28–2.21 (m, 1 H), 2.04–1.98 (m, 1 H), 1.92–1.86 (m, 1 H), 1.66–1.62 (m, 1 H).

¹H NMR (600 MHz, CDCl₃): δ (minor) = 7.57–7.54 (m, 2 H), 7.39–7.32 (m, 3 H), 7.16–7.09 (m, 3 H), 6.87–6.83 (m, 1 H), 6.40 (s, 1 H), 6.13 (s, 1 H), 3.79 (s, 3 H), 2.83–2.78 (m, 1 H), 2.56–2.50 (m, 1 H), 2.50–2.45 (m, 1 H), 2.10–2.05 (m, 1 H), 1.78–1.72 (m, 2 H).

¹³C NMR (151 MHz, CDCl₃): δ (major) = 211.65 (C=O), 167.25 (C=O), 151.8 (C_q), 133.5 (C_q), 131.8 (C_q), 129.0 (CH_Ar), 128.9 (CH_Ar), 128.3 (2C, CH_Ar), 126.95 (CH_Ar), 128.1 (C_q), 125.8 (CH_Ar), 124.8 (2C, CH_Ar), 124.3 (CH_Ar), 99.8 (CH), 79.6 (CH), 70.3 (C_q), 53.2 (CH₃), 38.5 (CH₂), 27.1 (CH₂), 20.0 (CH₂).

¹³C NMR (151 MHz, CDCl₃): δ (minor) = 211.9 (C=O), 168.7 (C=O), 153.2 (C_q), 133.8 (C_q), 132.8 (C_q), 129.1 (CH_Ar), 128.5 (2C, CH_Ar), 128.4 (CH_Ar), 127.8 (C_q), 128.7 (CH_Ar), 125.15 (2C, CH_Ar), 124.3 (CH_Ar), 123.5 (CH_Ar), 100.1 (CH), 80.3 (CH), 64.7 (C_q), 53.2 (CH₃), 39.4 (CH₂), 28.4 (CH₂), 20.2 (CH₂).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₂H₂₀O₄Na: 371.1254; found: 371.1244.

2-Phenyl-2-(3-phenyl-1H-isochromen-1-yl)cyclohexan-1-one (3n)

Yield: 44 mg (40%); colorless solid; mp 138 °C; R_f = 0.51 (n-pentane/EtOAc, 10:1); dr = 2.7: 1.

IR (ATR): 3337, 3164, 3059, 3029, 2943, 2868, 2654, 2323, 2227, 2173, 2071, 1985, 1899, 1807, 1701, 1630, 1600, 1490, 1450, 1421, 1374, 1275, 1227, 1182, 1116, 1067, 1028, 971, 919, 854, 806, 763, 694 cm⁻¹.

¹H NMR (600 MHz, CD₃CN): δ (major) = 7.68 (m, 1 H), 7.46–7.42 (m, 2 H), 7.33–7.31 (m, 3 H), 7.24–7.20 (m, 2 H), 7.19–7.16 (m, 1 H), 7.08–7.06 (m, 3 H), 6.99 (d, J = 7.6 Hz, 1 H), 6.64 (t, J = 7.6 Hz, 1 H), 6.33 (s, 1 H), 6.23 (s, 1 H), 5.54 (d, J = 7.7 Hz, 1 H), 2.60 (m, 1 H), 2.33 (m, 1 H), 2.30–2.16 (m, 1 H), 1.84 (m, 1 H), 1.67–1.61 (m, 2 H), 1.55 (m, 1 H).

¹H NMR (600 MHz, CD₃CN): δ (minor) = 7.70 (m, 1 H), 7.41–7.37 (m, 3 H), 7.30–7.28 (m, 1 H), 7.28–7.25 (m, 3 H), 7.13 (dd, J = 8.1, 1.4 Hz, 2 H), 7.10–7.08 (m, 2 H), 7.03 (d, J = 7.4 Hz, 1 H), 6.91 (d, J = 4.6 Hz, 1 H), 6.17 (s, 1 H), 6.13 (s, 1 H), 2.70 (m, 1 H), 2.30–2.16 (m, 2 H), 1.84 (m, 2 H), 1.67–1.61 (m, 2 H), 1.55 (m, 1 H).

¹³C NMR (151 MHz, CDCl₃): δ (major) = 210.4, 153.1, 136.3, 135.1, 132.9, 129.8, 129.65, 129.5, 129.3 (2C), 129.1, 128.8, 128.6, 127.7, 126.05, 125.6, 124.45, 100.6, 81.3, 79.0, 66.75, 41.0, 30.9, 30.1, 28.1, 27.5, 21.7.

¹³C NMR (151 MHz, CDCl₃): (minor) = 212.1, 153.2, 138.3, 135.1, 132.9, 129.8, 129.5, 129.4 (2C), 129.3, 128.9, 128.1, 127.9, 126.9, 126.4, 125.6, 124.8, 100.5, 82.0, 79.0, 66.75, 41.0, 30.9, 30.1, 28.1, 27.5, 22.0.

HRMS (ESI): m/z [M⁺] calcd for C₂₇H₂₄O₂: 380.1771; found: 380.1774.

Methyl 1-(6-Fluoro-3-p-tolyl-1H-isochromen-1-yl)-2-oxocyclopentanecarboxylate (3o)

Yield: 146 mg (96%); colorless solid; mp 75–77 °C; R_f = 0.5 (n-pentane/EtOAc, 85:15); dr = 1:1.

IR (ATR): 2933, 2651, 2542, 2099, 1917, 1698, 1424, 1266, 1106, 946, 823, 754 cm⁻¹.

¹H NMR (600 MHz, CDCl₃): δ (major) = 7.47 (d, J = 8.2 Hz, 2 H), 7.43 (d, J = 8.2 Hz, 2 H), 6.91 (dd, J = 9.2, 5.4 Hz, 1 H), 6.78 (ddd, J = 7.1, 6.5, 4.5 Hz, 2 H), 6.28 (s, 1 H), 6.20 (s, 1 H), 3.79 (s, 3 H), 2.76 (dd, J = 12.5, 7.4 Hz, 1 H), 2.55–2.48 (m, 1 H), 2.43 (dd, J = 9.8, 6.1 Hz, 1 H), 2.36 (s, 3 H), 2.29–2.21 (m, 1 H), 2.09–1.96 (m, 2 H).

¹H NMR (600 MHz, CDCl₃): δ (minor) = 7.18 (dd, J = 8.0, 3.3 Hz, 4 H), 6.81–6.76 (m, 3 H), 6.39 (s, 1 H), 6.07 (s, 1 H), 3.88 (s, 3 H), 2.70–2.64 (m, 1 H), 2.36 (s, 3 H), 1.90–1.81 (m, 1 H), 1.79–1.71 (m, 2 H), 1.67 (t, J = 9.2 Hz, 1 H), 1.28 (ddd, J = 14.6, 11.9, 5.6 Hz, 1 H).

¹³C NMR (151 MHz, CDCl₃): δ (major) = 211.6 (C=O), 167.1 (C=O), 162.8 (d, J = 246 Hz, CF), 152.9 (C_q), 139.7 (C_q), 134.3 (d, J = 9 Hz, C_q), 130.3 (C_q), 129.3 (2C, CH_Ar), 127.5 (d, J = 9 Hz, CH_Ar), 125.3 (2C, CH_Ar), 123.2 (d, J = 3, C_q), 112.8 (d, J = 22.6 Hz, CH_Ar), 110.6 (d, J = 22.6 Hz, CH_Ar), 99.6 (CH), 79.9 (CH), 70.4 (C_q), 53.8 (CH₃), 39.3 (CH₂), 28.3 (CH₂), 21.4 (CH₃), 20.1 (CH₂).

¹³C NMR (151 MHz, CDCl₃): δ (minor) = 211.7 (C=O), 168.6 (C=O), 163.05 (d, J = 246 Hz, CF), 154.4 (C_q), 139.5 (C_q), 135.3 (d, J = 9 Hz, C_q), 130.6 (C_q), 129.1 (2C, CH_Ar), 125.1 (d, J = 9 Hz, CH_Ar), 124.9 (2C, CH_Ar), 121.6 (d, J = 3, C_q), 113.9 (d, J = 22.6 Hz, CH_Ar), 110.6 (d, J = 22.6 Hz, CH_Ar), 99.5 (CH), 79.3 (CH), 64.8 (C_q), 53.1 (CH₃), 38.4 (CH₂), 27.3 (CH₂), 21.35 (CH₃), 19.9 (CH₂).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₃H₂₁O₄FNa: 403.1316; found: 403.1312.

2-[6-Fluoro-3-(p-tolyl)-1H-isochromen-1-yl]-2-phenylcyclohexan-1-one (3p)

Yield: 70 mg (59%); colorless solid; mp 158 °C; R_f = 0.43 (n-pentane/EtOAc, 10:1); dr = 2:1.

For crystal growth, a preparative HPLC was used to purify one diastereomer.

Preparative HPLC (RP) [Multospher 120 RP 18 HP (250 × 20 mm); water/MeOH, 1:9; 18 mL/ min; λ = 254 nm]: t_R = 20.8 (major), 22.6 (minor) min.

IR (ATR): 3393, 2940, 2322, 2085, 1889, 1702, 1604, 1477, 1231, 1065, 959, 799, 700 cm⁻¹.

¹H NMR (600 MHz, CD₃CN): δ = 7.59–7.55 (m, 2 H), 7.34–7.28 (m, 3 H), 7.26 (d, J = 8.0 Hz, 2 H), 7.05–7.02 (m, 2 H), 6.70 (dd, J = 9.7, 2.7 Hz, 1 H), 6.36 (t, J = 8.7 Hz, 1 H), 6.22 (s, 1 H), 6.20 (s, 1 H), 5.55 (dd, J = 8.5, 5.7 Hz, 1 H), 2.63–2.58 (m, 1 H), 2.37 (s, 3 H), 2.34–2.29 (m, 1 H), 2.21–2.16 (m, 2 H), 1.82 (m, 1 H), 1.62 (m, 2 H), 1.59–1.48 (m, 1 H).

¹³C NMR (151 MHz, CD₃CN): δ = 210.5, 164.2, 162.6, 154.4, 140.5, 136.1, 135.6, 132.0, 130.3 (2C), 129.7 (2C), 129.6, 129.6, 129.3 (2C), 128.7, 125.9 (2C), 122.2, 112.1, 110.2, 99.2, 66.8, 41.0, 28.4, 27.7, 21.8.

¹⁹F NMR (564 MHz, CD₃CN): δ = −111.55.

HRMS (ESI): m/z [M⁺] calcd for C₂₈H₂₅O₂F: 412.1833; found: 412.1836.

2-Acetyl-2-(6-fluoro-3-p-tolyl-1H-isochromen-1-yl)cyclopent­enone (3q)

Yield: 107 mg (74%); colorless solid; mp 75–77 °C; R_f = 0.6 (n-pentane/EtOAc, 85:15); dr = 1.4:1.

IR (ATR): 3432, 2959, 2314, 2088, 1901, 1711, 1610, 1487, 1209, 1131, 1061, 974, 802, 731 cm⁻¹.

¹H NMR (600 MHz, CDCl₃): δ (major) = 7.37 (d, J = 8.2 Hz, 2 H), 7.17 (d, J = 8.0 Hz, 2 H), 6.92–6.87 (m, 1 H), 6.84–6.76 (m, 2 H), 6.50 (s, 1 H), 6.15 (s, 1 H), 2.71 (dd, J = 12.7, 3.1 Hz, 1 H), 2.58 (s, 3 H), 2.36 (s, 3 H), 2.19 (dt, J = 8.0, 4.9 Hz, 1 H), 1.72 (ddd, J = 33.3, 20.4, 11.3 Hz, 2 H), 1.60 (tt, J = 11.2, 5.5 Hz, 2 H).

¹H NMR (600 MHz, CDCl₃): δ (minor) = 7.44 (d, J = 8.2 Hz, 2 H), 7.19 (d, J = 8.0 Hz, 2 H), 6.84–6.76 (m, 2 H), 6.70 (dd, J = 8.3, 5.2 Hz, 1 H), 6.34 (s, 1 H), 5.96 (s, 1 H), 2.96–2.89 (m, 1 H), 2.52–2.45 (m, 1 H), 2.42 (dd, J = 19.4, 9.4 Hz, 1 H), 2.37 (s, 3 H), 2.35 (s, 3 H), 2.32 (dd, J = 9.2, 4.9 Hz, 1 H), 2.04–1.92 (m, 2 H).

¹³C NMR (151 MHz, CDCl₃): δ (major) = 213.1 (C=O), 199.5 (C=O), 163.05 (d, J = 246.13 Hz, CF), 152.9 (C_q), 139.6 (C_q), 134.1 (d, J = 9 Hz, C_q), 130.3 (C_q), 129.2 (2C, CH_Ar), 126.8 (d, J = 8.8 Hz, CH_Ar), 124.9 (2C, CH_Ar), 121.7 (C_q), 113.3 (d, J = 22 Hz, CH_Ar), 110.75 (d, J = 22.5, CH_Ar), 98.5 (CH), 79.4 (CH), 78.5 (C_q), 39.1 (CH₂), 25.9 (CH₃), 25.5 (CH₂), 21.3 (CH₃), 19.95 (CH₂).

¹³C NMR (151 MHz, CDCl₃): δ (minor) = 212.5 (C=O), 202.1 (C=O), 162.9 (d, J = 246.13 Hz, CH), 155.2 (C_q), 139.9 (C_q), 136.0 (d, J = 9 Hz, C_q), 130.2 (C_q), 129.3 (2C, CH_Ar), 125.5 (2C, CH_Ar), 124.7 (d, J = 8.8 Hz, CH_Ar), 123.3 (C_q), 112.8 (d, J = 22.1 Hz, CH_Ar), 110.75 (d, J = 22.5 Hz, CH_Ar), 100.1 (CH), 80.3 (CH), 72.3 (C_q), 39.7 (CH₂), 27.4 (CH₃), 26.9 (CH₂), 21.4 (CH₃), 20.0 (CH₂).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₃H₂₁O₃FNa: 387.1367; found: 387.1363.

Ethyl 1-(6-Fluoro-3-p-tolyl-1H-isochromen-1-yl)-2-oxocyclopentanecarboxylate (3r)

Yield: 129 mg (82%); colorless solid; mp 68–70 °C; R_f = 0.7 (n-pentane/EtOAc, 85:15); dr = 1.7:1.

IR (ATR): 3442, 2967, 2283, 2119, 1899, 1726, 1609, 1484, 1239, 1108, 820 cm⁻¹.

¹H NMR (600 MHz, CDCl₃): δ (major) = 7.43 (d, J = 8.2 Hz, 2 H), 7.17 (d, J = 8.2 Hz, 2 H), 6.83 (dd, J = 9.2, 5.3 Hz, 1 H), 6.81–6.75 (m, 2 H), 6.28 (s, 1 H), 6.06 (s, 1 H), 4.25 (q, J = 7.1 Hz, 2 H), 2.79–2.72 (m, 1 H), 2.52 (ddd, J = 18.3, 8.1, 3.9 Hz, 1 H), 2.46–2.38 (m, 2 H), 2.36 (s, 3 H), 2.10–1.96 (m, 2 H), 1.27 (t, J = 12 Hz, 3 H).

¹H NMR (600 MHz, CDCl₃): δ (minor) = 7.48 (d, J = 8.2 Hz, 2 H), 7.17 (d, J = 8.2 Hz, 2 H), 6.92 (dd, J = 9.1, 5.6 Hz, 1 H), 6.81–6.75 (m, 2 H), 6.40 (s, 1 H), 6.18 (s, 1 H), 4.38 (dq, J = 10.8, 7.1 Hz, 1 H), 4.31–4.26 (m, 1 H), 2.70–2.63 (m, 1 H), 2.36 (s, 3 H), 2.29–2.21 (m, 1 H), 1.90–1.83 (m, 1 H), 1.79–1.70 (m, 2 H), 1.67 (dd, J = 7.9, 5.4 Hz, 1 H), 1.35 (t, J = 12 Hz, 3 H).

¹³C NMR (151 MHz, CDCl₃): δ (major) = 211.7 (C=O), 168.2 (C=O), 162.75 (J = 246.3 Hz, CF), 154.5 (C_q), 139.7 (C_q), 135.3 (d, J = 9 Hz, C_q), 130.4 (C_q), 129.25 (2C, CH_Ar), 125.3 (2C, CH_Ar), 125.3 (d, J = 9 Hz, CH_Ar), 123.3 (d, J = 3 Hz, C_q), 112.7 (d, J = 21 Hz, CH_Ar), 110.6 (d, J = 21 Hz, CH_Ar), 99.6 (CH), 79.95 (CH), 64.7 (C_q), 62.2 (CH₂), 39.3 (CH₂), 28.4 (CH₂), 20.2 (CH₂), 21.4 (CH₃), 14.0 (CH₃).

¹³C NMR (151 MHz, CDCl₃): δ (minor) = 211.7 (C=O), 166.6 (C=O), 163.0 (J = 246.3 Hz, CF), 153.1 (C_q), 139.5 (C_q), 134.3 (d, J = 9 Hz, C_q), 130.7 (C_q), 129.1 (2C, CH_Ar), 127.6 (d, J = 8 Hz, CH_Ar), 125 (2C, CH_Ar), 121.6 (d, J = 3 Hz, C_q), 113.1 (d, J = 21 Hz, CH_Ar), 110.5 (d, J = 21 Hz, CH_Ar), 98.5 (CH), 79.25 (CH), 70.4 (C_q), 62.2 (CH₂), 39.4 (CH₂), 27.1 (CH₂), 19.9 (CH₂), 21.4 (CH₃), 14.2 (CH₃).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₂₃O₄FNa: 417.1473; found: 417.1470.

Methyl 1-[3-(3-Fluorophenyl)-1H-isochromen-1-yl]-2-oxocyclopentanecarboxylate (3s)

Yield: 136 mg (93%); colorless solid; mp 99–101 °C; R_f = 0.6 (n-pentane/EtOAc, 85:15); dr = 1.7:1.

IR (ATR): 3380, 2954, 2742, 2329, 2095, 1902, 1698, 1591, 1469, 1254, 769 cm⁻¹.

¹H NMR (600 MHz, CDCl₃): δ (major) = 7.37 (d, J = 7.9 Hz, 1 H), 7.32 (d, J = 6.1 Hz, 1 H), 7.25 (d, J = 8.2 Hz, 2 H), 7.13–7.09 (m, 2 H), 7.02 (td, J = 7.9, 2.4 Hz, 1 H), 6.95 (d, J = 7.6 Hz, 1 H), 6.42 (s, 1 H), 6.30 (s, 1 H), 3.89 (s, 3 H), 2.70–2.64 (m, 1 H), 2.47–2.36 (m, 1 H), 2.29–2.21 (m, 1 H), 1.83 (ddd, J = 13.3, 11.0, 7.3 Hz, 1 H), 1.73 (tt, J = 12.6, 8.8 Hz, 2 H).

¹H NMR (600 MHz, CDCl₃): δ (minor) = 7.34–7.30 (m, 1 H), 7.28–7.24 (m, 1 H), 7.22 (dd, J = 11.9, 1.6 Hz, 1 H), 7.17–7.11 (m, 2 H), 7.02 (td, J = 7.9, 2.4 Hz, 1 H), 6.85 (d, J = 7.7 Hz, 1 H), 6.40 (s, 1 H), 6.12 (s, 1 H), 3.79 (s, 3 H), 2.84–2.75 (m, 1 H), 2.54 (ddd, J = 18.4, 8.1, 3.8 Hz, 1 H), 2.11–1.97 (m, 2 H), 1.68–1.59 (m, 2 H).

¹³C NMR (151 MHz, CDCl₃): δ (major) = 211.5 (C=O), 167.1 (C=O), 162.9 (d, J = 246.13 Hz, CF), 150.4 (C_q), 136.1 (d, J = 7.55 Hz, C_q), 131.3 (C_q), 129.8 (d, J = 8.2 Hz, CH_Ar), 129 (CH_Ar), 127.4 (CH_Ar), 126.3 (C_q), 125.8 (CH_Ar), 124.5 (CH_Ar), 120.3 (d, J = 1.5 Hz, CH_Ar), 115.6 (d, J = 23 Hz, CH_Ar), 111.7 (d, J = 16.6 Hz, CH_Ar), 100.8 (CH), 79.6 (CH), 70.3 (C_q), 53.2 (CH₃), 38.4 (CH₂), 27.1 (CH₂), 19.95 (CH₂).

¹³C NMR (151 MHz, CDCl₃): δ (minor) = 211.7 (C=O), 167.9 (d, J = 223.5 Hz, CF), 163.7 (C=O), 151.9 (C_q), 135.8 (d, J = 7.55 Hz, C_q), 132.3 (C_q), 130.0 (d, J = 8.3 Hz, CH_Ar), 128.5 (CH_Ar), 127.9 (C_q), 127.1 (CH_Ar), 124.5 (CH_Ar), 123.55 (CH_Ar), 120.7 (d, J = 3 Hz, CH_Ar), 115.9 (d, J = 23 Hz, CH_Ar), 111.9 (d, J = 16.6 Hz, CH_Ar), 102.1 (CH), 80.3 (CH), 64.6 (C_q), 53.1 (CH₃), 39.3 (CH₂), 28.4 (CH₂), 20.1 (CH₂).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₂H₁₉O₄FNa: 389.1165; found: 389.1158.

2-[3-(3-Fluorophenyl)-1H-isochromen-1-yl]-2-phenylcyclohexan-1-one (3t)

Yield: 79 mg (66%); colorless solid; mp 132 °C; R_f = 0.71 (n-pentane/EtOAc, 10:1); dr = 2:1.

IR (ATR): 3387, 3064, 3029, 2944, 2867, 2656, 2324, 2286, 2222, 2185, 2107, 2035, 1983, 1945, 1877, 1807, 1701, 1610, 1582, 1486, 1447, 1373, 1303, 1270, 1221, 1160, 1115, 1063, 992, 922, 871, 808, 783, 745, 697 cm⁻¹.

¹H NMR (600 MHz, CD₃CN): δ (major) = 7.51 (m, 1 H), 7.45 (td, J = 8.0, 5.9 Hz, 1 H), 7.39 (m, 1 H), 7.34–7.29 (m, 3 H), 7.16–7.12 (m, 3 H), 7.07–7.04 (m, 3 H), 6.67 (td, J = 7.6, 1.3 Hz, 1 H), 6.38 (s, 1 H), 6.23 (s, 1 H), 5.57 (d, J = 7.6 Hz, 1 H), 2.59 (dq, J = 14.6, 3.1 Hz, 1 H), 2.35–2.29 (m, 1 H), 2.22–2.15 (m, 1 H), 1.86 (m, 1 H), 1.66–1.62 (m, 3 H).

¹H NMR (600 MHz, CD₃CN): δ (minor) = 7.53 (m, 1 H), 7.28–7.26 (m, 1 H), 7.25–7.20 (m, 3 H), 7.20–7.17 (m, 1 H), 7.12–7.08 (m, 3 H), 7.01–6.99 (m, 3 H), 7.01–6.99 (m, 1 H), 6.20 (s, 1 H), 6.16 (s, 1 H), 5.99 (d, J = 8.2 Hz, 1 H), 2.68 (dq, J = 14.6, 3.2 Hz, 1 H), 2.25 (dt, J = 14.3, 3.4 Hz, 1 H), 2.22–2.15 (m, 1 H), 1.83 (m, 2 H), 1.60–1.49 (m, 2 H).

¹³C NMR (151 MHz, CD₃CN): δ (major) = 210.5, 137.7, 136.2, 132.5, 131.4, 130.7, 129.7, 129.3, 128.9, 128.7, 127.8, 127.4, 126.5, 125.0, 124.7, 121.5, 116.4, 115.9, 112.3, 101.8, 81.4, 79.0, 66.7, 41.0, 28.3, 27.6, 21.7.

¹³C NMR (151 MHz, CD₃CN): δ (minor) = 212.1, 137.7, 136.2, 132.5, 131.4, 130.6, 129.4, 129.1, 128.1, 128.0, 127.8, 127.6, 126.6, 125.05, 121.35, 116.2, 115.8, 112.3, 112.1, 101.7, 81.4, 79.0, 66.7, 41.0, 31.0, 28.1, 21.95.

¹⁹F NMR (564 MHz, CD₃CN): δ = −114.48 (major), −115.15 (minor).

HRMS (ESI): m/z [M⁺] calcd for C₂₇H₂₃O₂F: 398.1677; found: 398.1678.

Methyl 1-(7-Methoxy-3-phenyl-1H-isochromen-1-yl)-2-oxocyclopentanecarboxylate (3u)

Yield: 137 mg (91%); colorless solid; mp 114–116 °C; R_f = 0.45 (n-pentane/EtOAc, 85:15); dr = 1.25:1.

IR (ATR): 3809, 3357, 2932, 2841, 2748, 2336, 2091, 1901, 1683, 1590, 1479, 1292, 1222, 1153, 1021, 831, 748, 691 cm⁻¹.

¹H NMR (600 MHz, CDCl₃): δ (major) = 7.55 (d, J = 7.4 Hz, 2 H), 7.35 (t, J = 7.5 Hz, 2 H), 7.30 (t, J = 7.1 Hz, 1 H), 7.05 (d, J = 3.7 Hz, 1 H), 6.80 (t, J = 8.2 Hz, 1 H), 6.53 (d, J = 2.5 Hz, 1 H), 6.35 (s, 1 H), 6.26 (s, 1 H), 3.88 (s, 3 H), 3.76 (s, 3 H), 2.80–2.74 (m, 1 H), 2.53–2.48 (m, 1 H), 2.44–2.35 (m, 1 H), 2.06–1.96 (m, 1 H), 1.84–1.78 (m, 1 H), 1.65 (t, J = 4.9 Hz, 1 H).

¹H NMR (600 MHz, CDCl₃): δ (minor) = 7.52 (d, J = 7.4 Hz, 2 H), 7.35 (t, J = 7.5 Hz, 2 H), 7.30 (t, J = 7.1 Hz, 1 H), 7.05 (d, J = 3.7 Hz, 1 H), 6.80 (t, J = 8.2 Hz, 1 H), 6.45 (d, J = 2.4 Hz, 1 H), 6.38 (s, 1 H), 6.12 (s, 1 H), 3.80 (s, 3 H), 3.76 (s, 3 H), 2.68 (dd, J = 13.4, 6.2 Hz, 1 H), 2.48–2.44 (m, 1 H), 2.26 (dd, J = 18.6, 7.7 Hz, 1 H), 2.06–1.96 (m, 1 H), 1.89–1.84 (m, 1 H), 1.77–1.69 (m, 1 H).

¹³C NMR (151 MHz, CDCl₃): δ (major) = 211.8 (C=O), 168.65 (C=O), 158.8 (C_q), 149.75 (C_q), 133.7 (C_q), 128.5 (CH_Ar), 128.4 (CH_Ar, 2C), 127.7 (C_q), 125.6 (CH_Ar), 125.5 (C_q), 124.5 (CH_Ar, 2C), 114.75 (CH_Ar), 110.4 (CH_Ar), 99.5 (CH), 80.0 (CH),70.3 (C_q), 55.4 (CH₃), 53.1 (CH₃), 38.5 (CH₂), 27.1 (CH₂), 20.1 (CH₂).

¹³C NMR (151 MHz, CDCl₃): δ (minor) = 211.75 (C=O), 167.1 (C=O), 158.7 (C_q), 151.1 (C_q), 134.0 (C_q), 129.4 (C_q), 128.6 (CH_Ar), 128.3 (CH_Ar, 2C), 125.4 (CH_Ar), 124.7 (CH_Ar, 2C), 124.7 (C_q), 113.0 (CH_Ar), 111.2 (CH_Ar), 100.6 (CH), 79.6 (CH), 65.1 (C_q), 55.3 (CH₃), 53.1 (CH₃), 39.4 (CH₂), 28.3 (CH₂), 19.9 (CH₂).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₃H₂₂O₅Na: 401.1359; found: 401.1365.

2-(7-Methoxy-3-phenyl-1H-isochromen-1-yl)-2-phenylcyclohexan-1-one (3v)

Yield: 30 mg (37%); colorless oil; R_f = 0.43 (n-pentane/Et₂O, 6:2); dr = 1:1.

IR (ATR): 3940, 3791, 3388, 2893, 2671, 2310, 2092, 1863, 1349, 1040, 787 cm⁻¹.

¹H NMR (600 MHz, CD₃CN): δ (major) = 7.66 (d, J = 7.6 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 1 H), 7.23 (dd, J = 9.5, 6.1 Hz, 4 H), 7.18 (d, J = 8.1 Hz, 3 H), 7.08 (d, J = 7.4 Hz, 2 H), 6.99 (d, J = 8.3 Hz, 1 H), 6.78 (d, J = 2.7 Hz, 1 H), 6.16 (s, 1 H), 6.14 (s, 1 H), 3.79 (s, 3 H), 2.72 (m, 1 H), 2.29–2.24 (m, 2 H), 1.87–1.80 (m, 2 H), 1.64–1.61 (m, 2 H), 1.54 (m, 1 H).

¹H NMR (600 MHz, CD₃CN): δ (minor) = 7.4–7.3 (m, 3 H), 7.3 (t, J = 7.4 Hz, 2 H), 7.2 (s, 1 H), 7.1–7.1 (m, 2 H), 6.9 (d, J = 8.3 Hz, 1 H), 6.8 (dd, J = 8.4, 2.8 Hz, 1 H), 6.7–6.6 (m, 1 H), 6.3 (s, 1 H), 6.2 (s, 1 H), 5.1 (d, J = 2.4 Hz, 1 H), 3.3 (s, 3 H), 2.6 (m, 1 H), 2.4–2.3 (m, 1 H), 2.2–2.2 (m, 2 H), 1.9 (m, 2 H), 1.7–1.6 (m, 2 H), 1.6 (m, 1 H).

¹³C NMR (151 MHz, CD₃CN): δ (major) = 212.2, 159.2, 151.2, 138.3, 134.9, 129.8, 129.5, 129.4 (2C), 129.1 (2C), 128.8 (2C), 128.0, 126.0, 125.7, 125.2 (2C), 114.2, 114.1, 100.2, 81.7, 64.8, 56.0, 41.0, 28.0, 27.4, 22.0.

¹³C NMR (151 MHz, CD₃CN): δ (minor) = 210.2, 158.2, 151.2, 136.6, 135.3, 130.0, 129.7, 129.4 (2C), 129.3 (2C), 129.0 (2C), 128.7, 126.6, 125.7, 125.3 (2C), 115.3, 112.6, 100.3, 81.4, 66.7, 55.4, 41.0, 30.7, 27.8, 21.7.

HRMS (ESI): m/z [M⁺] calcd for C₂₈H₂₆O₃: 410.1876; found: 410.1875.

Methyl 1-[3-(4-tert-Butylphenyl)-1H-isochromen-1-yl]-2-oxocyclopentanecarboxylate (3w)

Yield: 146 mg (90%); colorless solid; mp 89–91 °C; R_f = 0.65 (n-pentane/EtOAc, 85:15); dr = 1.1:1.

IR (ATR): 3425, 2955, 2310, 2084, 2926, 1728, 1445, 1233, 1100, 814 cm⁻¹.

¹H NMR (600 MHz, CDCl₃): δ (major) = 7.53 (d, J = 8.5 Hz, 2 H), 7.50 (d, J = 8.5 Hz, 2 H), 7.27–7.21 (m, 1 H), 7.15–7.08 (m, 2 H), 6.84 (d, J = 7.6 Hz, 1 H), 6.37 (s, 1 H), 6.25 (s, 1 H), 3.79 (s, 3 H), 2.80 (dd, J = 16.3, 7.4 Hz, 1 H), 2.57–2.50 (m, 1 H), 2.50–2.39 (m, 2 H), 1.78 (dd, J = 18.5, 7.4 Hz, 1 H), 1.66–1.58 (m, 1 H), 1.33 (s, 9 H).

¹H NMR (600 MHz, CDCl₃): δ (minor) = 7.40 (dd, J = 8.6, 1.9 Hz, 4 H), 7.27–7.21 (m, 1 H), 7.15–7.08 (m, 2 H), 6.95 (d, J = 8.0 Hz, 1 H), 6.44 (s, 1 H), 6.11 (s, 1 H), 3.92 (s, 3 H), 2.74–2.67 (m, 1 H), 2.29–2.21 (m, 1 H), 2.04–1.99 (m, 1 H), 1.90 (dd, J = 20.3, 10.5 Hz, 1 H), 1.80–1.71 (m, 2 H), 1.34 (s, 9 H).

¹³C NMR (151 MHz, CDCl₃): δ (major) = 211.7 (C=O), 168.8 (C=O), 152.4 (C_q), 152.0 (C_q), 132.0 (C_q), 130.7 (C_q), 128.4 (CH_Ar), 127.8 (C_q), 126.45 (CH_Ar), 125.45 (2C, CH_Ar), 125.0 (2C, CH_Ar), 124.1 (CH_Ar), 123.4 (CH_Ar), 100.4 (CH), 80.3 (CH), 70.4 (C_q), 53.2 (CH₃), 38.6 (CH₂), 34.7 (C_q), 31.2 (3C, tert-butyl), 28.4 (CH₂), 20.2 (CH₂).

¹³C NMR (151 MHz, CDCl₃): δ (minor) = 211.9 (C=O), 167.3 (C=O), 153.4 (C_q), 152.2 (C_q), 133.0 (C_q), 131.0 (C_q), 128.9 (CH_Ar), 126.7 (CH_Ar), 126.05 (C_q), 125.8 (CH_Ar), 125.3 (2C, CH_Ar), 124.7 (2C, CH_Ar), 124.2 (CH_Ar), 99.2 (CH), 79.6 (CH), 64.6 (C_q), 53.1 (CH₃), 39.4 (CH₂), 34.7 (C_q), 31.2 (3C, tert-butyl), 27.1 (CH₂), 19.2 (CH₂).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₆H₂₈O₄Na: 427.188; found: 427.187.

2-{3-[4-(tert-Butyl)phenyl]-1H-isochromen-1-yl}-2-phenylcyclohexan-1-one (3x)

Yield: 71 mg (54 %); colorless solid; mp 141.0 °C; R_f = 0.77 (pentane/EtOAc, 15:1); dr = 2.2:1.

IR (ATR): 3828, 3456, 3021, 2953, 2870, 2653, 2320, 2182, 2086, 1983, 1913, 1729, 1632, 1595, 1449, 1366, 1268, 1216, 1115, 1065, 925, 828, 795, 743, 694 cm⁻¹.

¹H NMR (600 MHz, CD₃CN): δ (major) = 7.63–7.59 (m, 2 H), 7.50–7.46 (m, 2 H), 7.34–7.29 (m, 2 H), 7.27–7.24 (m, 2 H), 7.09–7.02 (m, 3 H), 6.62 (tt, J = 7.5, 0.9 Hz, 1 H), 6.29 (s, 1 H), 6.22 (s, 1 H), 5.52 (d, J = 7.7 Hz, 1 H), 2.59 (dq, J = 14.7, 3.2 Hz, 1 H), 2.33 (dt, J = 14.2, 3.3 Hz, 1 H), 2.30–2.15 (m, 2 H), 1.84 (m, 1 H), 1.64 (m, 2 H), 1.55 (m, 1 H), 1.33 (d, J = 0.7 Hz, 9 H, CH₃).

¹H NMR (600 MHz, CD₃CN): δ (minor) = 7.34–7.29 (m, 4 H), 7.22–7.15 (m, 5 H), 7.09–7.02 (m, 3 H), 6.97 (d, J = 7.6 Hz, 1 H), 6.16 (s, 1 H), 6.09 (s, 1 H), 2.72 (dq, J = 14.7, 3.2 Hz, 1 H), 2.30–2.15 (m, 2 H), 2.2 (m, 1 H), 1.84 (m, 1 H), 1.64 (m, 2 H), 1.55 (m, 1 H), 1.28 (d, J = 0.7 Hz, 9 H, CH₃).

¹³C NMR (151 MHz, CD₃CN): δ (major) = 210.3, 153.2, 153.1, 136.3, 133.1, 132.3, 129.6, 129.3, 129.0, 128.8 (2C), 128.6 (2C), 127.7, 126.5, 125.8 (2C), 125.4, 124.3 (2C), 100.0, 81.3, 66.8, 41.0, 35.3, 31.4 (3C), 28.1, 27.5, 21.7.

¹³C NMR (151 MHz, CD₃CN): δ (minor) = 212.0, 153.5, 152.8, 138.4, 134.1, 131.9, 129.4 (2C), 129.0 (2C), 128.2, 128.1, 127.9, 126.8, 126.3 (2C), 125.5 (2C), 124.7, 118.3, 100.0, 82.1, 64.3, 41.0, 35.2, 31.4 (3C), 30.5, 27.9, 22.0.

HRMS (ESI): m/z [M⁺] calcd for C₃₁H₃₂O₂: 436.2397; found: 436.2398.

Methyl 1-[3-(4-Methoxyphenyl)-1H-isochromen-1-yl]-2-oxocyclopentanecarboxylate (3y)

Yield: 139 mg (92%); colorless solid; mp 108–110 °C; R_f = 0.40 (n-pentane/EtOAc, 85:15); dr = 1.5:1.

IR (ATR): 3447, 2949, 2609, 2325, 2087, 1906, 1725, 1602, 1487, 1249, 1032, 940, 799 cm⁻¹.

¹H NMR (600 MHz, CDCl₃): δ (major) = 7.52 (d, J = 9.0 Hz, 2 H), 7.25–7.22 (m, 1 H), 7.09–7.06 (m, 2 H), 6.93 (d, J = 7.5 Hz, 1 H), 6.88 (d, J = 2.2 Hz, 2 H), 6.40 (s, 1 H), 6.17 (s, 1 H), 3.89 (s, 3 H), 3.82 (s, 3 H), 2.71–2.65 (m, 1 H), 2.45–2.36 (m, 1 H), 2.27–2.21 (m, 1 H), 1.91–1.85 (m, 1 H), 1.79–1.68 (m, 2 H).

¹H NMR (600 MHz, CDCl₃): δ (minor) = 7.48 (d, J = 9.0 Hz, 2 H), 7.25–7.22 (m, 1 H), 7.13–7.09 (m, 2 H), 6.90 (d, J = 2.2 Hz, 2 H), 6.83 (d, J = 7.6 Hz, 1 H), 6.27 (s, 1 H), 6.08 (s, 1 H), 3.82 (s, 3 H), 3.79 (s, 3 H), 2.83–2.77 (m, 1 H), 2.55–2.45 (m, 2 H), 2.01 (dd, J = 10.4, 6.6 Hz, 1 H), 1.67–1.59 (m, 2 H).

¹³C NMR (151 MHz, CDCl₃): δ (major) = 211.7 (C=O), 168.7 (C=O), 160.3 (C_q), 151.7 (C_q), 132.1 (C_q), 128.9 (CH_Ar), 127.55 (C_q), 126.5 (CH_Ar), 126.35 (CH_Ar, 2C), 125.85 (C_q), 125.8 (CH_Ar), 124.0 (CH_Ar), 113.7 (CH_Ar, 2C), 98.3 (CH), 79.6 (CH), 70.4 (C_q), 55.3 (CH₃), 53.15 (CH₃), 38.5 (CH₂), 27.1 (CH₂), 20.0 (CH₂).

¹³C NMR (151 MHz, CDCl₃): δ (minor) = 212.0 (C=O), 167.3 (C=O), 160.4 (C_q), 153.2 (C_q), 133.15 (C_q), 128.35 (CH_Ar), 126.7 (CH_Ar, 2C), 126.5 (C_q), 126.2 (CH_Ar), 126.2 (C_q), 123.9 (CH_Ar), 123.4 (CH_Ar), 113.9 (CH_Ar, 2C), 99.5 (CH), 80.2 (CH), 64.6 (C_q), 55.3 (CH₃), 53.1 (CH₃), 39.4 (CH₂), 28.4 (CH₂), 20.2 (CH₂).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₃H₂₂O₅Na: 401.1359; found: 401.1357.

2-Phenyl-2-[3-(p-tolyl)-1H-isochromen-1-yl]cyclohexan-1-one (3z)

Yield: 32 mg (52%); yellow oil; R_f = 0.40 (pentane/Et₂O, 7:2); dr = 9:1.

IR (ATR): 3620, 2942, 2312, 2095, 1735, 1599, 1461, 1157, 758 cm⁻¹.

¹H NMR (600 MHz, CD₃CN): δ = 7.51–7.49 (m, 2 H), 7.31 (m, 4 H), 7.23–7.20 (m, 3 H), 7.16–7.12 (m, 2 H), 6.84–6.81 (m, 2 H), 6.44 (s, 1 H), 6.03 (d, J = 10.6 Hz, 1 H), 4.23 (dd, J =10.7, 5.5 Hz, 1 H), 3.78 (s, 3 H), 3.04 (dt, J = 9.8, 4.6 Hz, 1 H), 2.55–2.33 (m, 1 H), 2.20 (m, 2 H), 1.79 (dt, J = 12.3, 4.5 Hz, 2 H), 1.72–1.66 (m, 1 H).

¹³C NMR (151 MHz, CD₃CN): δ = 211, 161.3, 151.35, 140, 131.75, 129.7, 129.6, 129.2, 129, 128.8, 127.65, 127.5, 126.7, 126.5, 124.9, 114.4, 99.3, 77.5, 55.9, 55.3, 53.0, 42.8, 35.9, 35.4, 29.9, 28.4, 26.0, 21.6.

HRMS (ESI): m/z [M⁺] calcd for C₂₈H₂₆O₃: 410.1876; found: 410.1875.

Methyl 1-(6-Chloro-3-phenyl-1H-isochromen-1-yl)-2-oxocyclopentanecarboxylate (3a′)

Yield: 141 mg (92%); colorless solid; mp 89–91 °C; R_f = 0.5 (n-pentane/EtOAc, 85:15); dr = 1.1:1.

IR (ATR): 3459, 2957, 2647, 2288, 2105, 2008, 1921, 1725, 1594, 1481, 1446, 1405, 1231, 1109, 1061, 975, 915, 819, 762, 690 cm⁻¹.

¹H NMR (600 MHz, CDCl₃): δ (major) = 7.53 (d, J = 8.2 Hz, 2 H), 7.37 (m, 3 H), 7.11–7.05 (m, 2 H), 6.77 (d, J = 9.2 Hz, 1 H), 6.32 (s, 1 H), 6.22 (s, 1 H), 3.79 (s, 3 H), 2.80–2.73 (m, 1 H), 2.53 (ddd, J = 18.4, 8.1, 4.0 Hz, 1 H), 2.10–1.97 (m, 2 H), 1.88–1.80 (m, 1 H), 1.80–1.59 (m, 1 H).

¹H NMR (600 MHz, CDCl₃): δ (minor) = 7.57 (dt, J = 5.6, 4.4 Hz, 2 H), 7.37 (m, 3 H), 7.11–7.05 (m, 2 H), 6.88 (d, J = 7.9 Hz, 1 H), 6.40 (s, 1 H), 6.07 (s, 1 H), 3.88 (s, 3 H), 2.71–2.65 (m, 1 H), 2.40 (ddd, J = 28.3, 15.7, 9.0 Hz, 2 H), 2.31–2.22 (m, 1 H), 1.80–1.59 (m, 2 H).

¹³C NMR (151 MHz, CDCl₃): δ (major) = 211.5 (C_q), 168.55 (C_q), 154.4 (C_q), 134.7 (C_q), 133.7 (C_q), 133.1 (C_q), 129.5 (CH_Ar), 128.6 (CH_Ar, 2C), 126.3 (CH_Ar), 125.9 (C_q), 125.3 (CH_Ar, 2C), 124.9 (CH_Ar), 123.95 (CH_Ar), 100.05 (CH), 98.85 (CH), 64.6 (C_q), 53.1 (CH₃), 39.3 (CH₂), 28.3 (CH₂), 19.9 (CH₂).

¹³C NMR (151 MHz, CDCl₃): δ (minor) = 211.5 (C_q), 167 (C_q), 153.0 (C_q), 134.7 (C_q), 134.3 (C_q), 133.4 (C_q), 129.4 (CH_Ar, 2C), 128.4 (CH_Ar), 127.2 (CH_Ar), 126.65 (CH_Ar), 125 (CH_Ar 2C), 124.3 (C_q), 123.95 (CH_Ar), 79.9 (CH), 79.2 (CH), 70.3 (C_q), 53.1 (CH₃), 38.4 (CH₂), 27.1 (CH₂), 20.1 (CH₂).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₂H₁₉O₄ClNa: 405.0864; found: 405.0860.

Acknowledgment

Financial support from the European Research Council (ERC Advanced Grant 320493 ‘DOMINOCAT’) is gratefully acknowledged.

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